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US3892754A - 5,6-Benzo-{65 -pyridone derivatives - Google Patents

5,6-Benzo-{65 -pyridone derivatives Download PDF

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US3892754A
US3892754A US206922A US20692271A US3892754A US 3892754 A US3892754 A US 3892754A US 206922 A US206922 A US 206922A US 20692271 A US20692271 A US 20692271A US 3892754 A US3892754 A US 3892754A
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Ekkehard Winterfeldt
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • 5,6-benzo-y-pyridone derivatives can be converted by reduction into quinoline derivatives of which important representatives occur in nature with pharmacological properties, for example as substances inhibiting tumors.
  • An important member of this series is camptothecine of the formula:
  • R is H or CH
  • R is a radical conventional for esterification, particularly lower alkyl, or higher alkyl, benzyl or phenyl;
  • R is a radical like R, again particularly lower alkyl
  • the alkali metals on which the proton acceptors are based are usually lithium, sodium and potassium, and the alkaline earth metals are magnesium and calcium.
  • alcohols those having up to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl or t-butyl alcohol, secondary or tertiary alkoxides of the said metals, and also higher alcohols or glycols.
  • hydrides are lithium, sodium and calcium hydride.
  • Suitable acetylides are for example sodium and calcium acetylides.
  • amides are lithium amide, sodium amide, lithium piperidide, and lithium di-isopropylamide.
  • Grignard compounds those which are sterically hindered are preferred, e.g. 0,0-dimethylphenyl-Mg-halide.
  • Sterically hindered tertiary amines including for example ethyl diisopropylamine and diazabicyclooctane. are described in German Pat. No. 1,132,135.
  • Strongly basic ion exchangers are for example those having quaternary trialkylammonium groups and being commercially available under the names LEWATIT M500, M600, MPSOO, and MP5080, AMBERLIT 1RA 400 and IRA 401, and DOWEX 1 and 2.
  • quaternary ammonium hydroxide which is suitable for the purposes of the process of this invention is trimethylbenzyl ammonium hydroxide.
  • the proton acceptor as such to the reaction medium, but (like sodium hydride) as a suspension in an inert liquid, e.g. spindle oil or naphtha.
  • Oxygen, air or mixtures of oxygen and other gases may be used as the oxidizing agent for the process of the invention.
  • the oxidation only proceeds in the .desired direction however when a proton acceptor is present in the reaction mixture.
  • Potassium t-butylate and sodium hydride are particularly preferred.
  • The. oxida' tion combined with a rearrangement of the ring is carried out in a liquid medium.
  • Suitable liquids for this purpose include polar organic solvents or liquids which do not take part in or interfere with the reaction such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide or also for example alcohols which are liquid at the reaction temperature. Mixtures of such liquids are also suitable. It is preferred to use dimethylformamide.
  • the reaction temperature may be room temperature. for example from 15 to 30C. lf longer reaction periods are tolerable, a temperature of about 0C is suitable. Shorter reaction periods may be achieved by gentle heating, for example to about 50C.
  • the reaction may be carried out for example by dissolving the indole derivative in a solvent of the said type, adding an equimolar amount or twice the equimolar amount of a proton acceptor, flushing oxygen or air through and leaving the mixture for from 1 hour to 3 hours at about 18 to 25C.
  • the whole is then poured into about 4 times the amount of the reaction mixture of icewater which contains about 2% of an acid, preferably acetic acid, for decomposition of the proton acceptor, adjusted to apH of from 7 to 8, preferably about 7.5, with an alkaline solution such as saturated sodium carbonate solution and the pyridone derivative is extracted with an extractant by a known method, for example with methylene chloride.
  • the course of the oxidation up to the end point may if desired be followed by infrared spectroscopy of NMR measurements.
  • enol ether (V) 500 mg is dissolved in ccm of absolute dioxane and united under nitrogen with a solution of 300 mg of t-butyl malonate and 80 mg of sodium hydride in ccm of absolute dioxane. After 1 hour under reflux, decompositon is effected with dilute acetic acid and extraction with methylene chloride. The organic phase is shaken with saturated bicarbonate solution and then with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then evaporated off in vacuo.
  • R" denotes t-butyl Wl'llCll comprises subjecting an in- EXAMPLE 6 5O dole of the formula:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for producing 5,6- gamma -pyridone derivatives by oxidation of indole derivatives, and to 5,6- gamma -pyridine derivatives. In the process, compounds of the Formula (II)

are prepared by treating compounds of the Formula (I)

D R A W I N G

Description

United States Patent 1191 A [111 r 3,892,754 Winterfeldt July 1, 1975 5,6-BENZO-y-PYRIDONE DERIVATIVES [75] Inventor: Ekkehard Winterfeldt, STRACT Gr rg Germany A method for producing 5,6-y-pyridone derivatives by 73 Assignee: Badische Anilin- & Soda-Fabrik Oxidation of indole derivatives, and to -v-py Aktiengesellschaft Ludwigshafen derivatives. In the process, compounds of the Formula (Rhine), Germany [22] Filed: Dec. 10, 1971 [21] Appl. No.: 206,922
[30] Foreign Application Priority Data Nov. 13, 197i Germany 2156501 Dec. 12, 1970 Germany 2061359 [52] U.S. Cl 260/287 R; 260/289 A; 260/295 C;
424/258 Int. are prepared treating compounds of the Formul [58] Field of Search 260/287 R, 289 A, 283 SY (I) [56] References Cited UNITED STATES PATENTS R' 3,234,142 2/1966 Wolfrum 260/287 R O (I) 3,634346 1/1972 McKeon 260/289 R H 1 OTHER PUBLICATIONS OOH Winterfeldt et al., Chem. Commun., vol. 1971, p. 374-375. chemand News July 111 1966 with oxygen in the presence of a proton acceptor.
Chem and g- News, December 121 1966 P- 6468- The compounds are useful in producing quinoline derivatives which have important pharmacological prop- Primary ExaminerDonald G. Daus erties Attorney, Agent, or FirmJohnston, Keil, Thompson & Shurtleff 1 Claim, No Drawings 1 5,6-BENZO-y-PYRIDONE DERIVATIVES The invention relates to the production of 5,6-ypyridone derivatives by oxidation of indole derivatives, and to 5,6-'y-pyridine derivatives.
5,6-benzo-y-pyridone derivatives can be converted by reduction into quinoline derivatives of which important representatives occur in nature with pharmacological properties, for example as substances inhibiting tumors. An important member of this series is camptothecine of the formula:
There has therefore been a need for a method of re action to be found which permits the oxidation of indole derivatives with low expenditure and moreover permits the production of derivatives which conform to the structure of the natural substances or closely approximate thereto.
1 have found that from compounds of the formula (1):
lyuul c O in which R is H or CH R is a radical conventional for esterification, particularly lower alkyl, or higher alkyl, benzyl or phenyl;
R is 011 (la), -HC=(COOR) (lb), O alkyl or CH COOR, and
R is a radical like R, again particularly lower alkyl,
form compounds of the formula (11):
I N O N I 1 H cooa droxides. Mixtures of two or more of the said proton acceptors may also be used.
For practical reasons, the alkali metals on which the proton acceptors are based are usually lithium, sodium and potassium, and the alkaline earth metals are magnesium and calcium.
in general it is convenient to use as alcohols those having up to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl or t-butyl alcohol, secondary or tertiary alkoxides of the said metals, and also higher alcohols or glycols.
Examples of hydrides are lithium, sodium and calcium hydride. Suitable acetylides are for example sodium and calcium acetylides. Examples of amides are lithium amide, sodium amide, lithium piperidide, and lithium di-isopropylamide. Of the Grignard compounds those which are sterically hindered are preferred, e.g. 0,0-dimethylphenyl-Mg-halide. Sterically hindered tertiary amines, including for example ethyl diisopropylamine and diazabicyclooctane. are described in German Pat. No. 1,132,135.
Strongly basic ion exchangers are for example those having quaternary trialkylammonium groups and being commercially available under the names LEWATIT M500, M600, MPSOO, and MP5080, AMBERLIT 1RA 400 and IRA 401, and DOWEX 1 and 2.
An example of a quaternary ammonium hydroxide which is suitable for the purposes of the process of this invention is trimethylbenzyl ammonium hydroxide. In many cases it may be advantageous not to add the proton acceptor as such to the reaction medium, but (like sodium hydride) as a suspension in an inert liquid, e.g. spindle oil or naphtha.
The following Examples serve to illustrate the invention which will be readily understood by those skilled in the art after reading the present specification.
The Examples may be modified in many ways without departing from the spirit of this invention.
Starting compound with R denoting OH (la) may be obtained by reacting the ester having the formula (11]):
M W @i l' CH COOC H (III) (GB. Kline, J. Am. Chem. Soc. 81, 2251 (1959)) with a monoalkyl malonate to form an ester of the formula (IV):
H CO
may be converted with thionyl chloride into the4- chloroquinoline derivatives (Vla) and (Vlb):
(Vla): R denotes Cl (Vlb): R denotes -HC=(COOR) The chlorine may be replaced by hydrogen by a known method reductively by means of a partially poisoned catalyst.
The following description is concerned with the production of compounds (11) by the process of this invention: I
Oxygen, air or mixtures of oxygen and other gases may be used as the oxidizing agent for the process of the invention. The oxidation only proceeds in the .desired direction however when a proton acceptor is present in the reaction mixture. Potassium t-butylate and sodium hydride are particularly preferred. The. oxida' tion combined with a rearrangement of the ring is carried out in a liquid medium. Suitable liquids for this purpose include polar organic solvents or liquids which do not take part in or interfere with the reaction such as dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide or also for example alcohols which are liquid at the reaction temperature. Mixtures of such liquids are also suitable. It is preferred to use dimethylformamide.
The reaction temperature may be room temperature. for example from 15 to 30C. lf longer reaction periods are tolerable, a temperature of about 0C is suitable. Shorter reaction periods may be achieved by gentle heating, for example to about 50C.
The reaction may be carried out for example by dissolving the indole derivative in a solvent of the said type, adding an equimolar amount or twice the equimolar amount of a proton acceptor, flushing oxygen or air through and leaving the mixture for from 1 hour to 3 hours at about 18 to 25C. The whole is then poured into about 4 times the amount of the reaction mixture of icewater which contains about 2% of an acid, preferably acetic acid, for decomposition of the proton acceptor, adjusted to apH of from 7 to 8, preferably about 7.5, with an alkaline solution such as saturated sodium carbonate solution and the pyridone derivative is extracted with an extractant by a known method, for example with methylene chloride. The course of the oxidation up to the end point may if desired be followed by infrared spectroscopy of NMR measurements.
' The process of the invention gives new 5,6 -benzo-ypyridines whose carbonyl groups can be reduced or can be chlorinated by reaction for example with phosphorus oxychloride. The chlorine atom may then be replaced in turn by other atoms or atomic groups. Ester groups may be hydrolyzed to the free carboxylic acid groups. All the compounds thus obtained are valuable intermediates for the pharmaceutical industry, particularly for the manufacture of tumorinhibiting agents.
When the pyridone oxygen is acylated. quinoline derivatives are formed which also have significance as antimalarial agents.
Production of (la):
6.6 g of the ethyl ester (III) is dissolved in 50 ccm of absolute methylene chloride, 3.5 g of monoethyl malonate is added and then a solution of 5.5 g of dicyclohexylcarbodiimide in 20 ccm of methylene chloride is dripped in rapidly. The urea precipitated is filtered off 1 hour later. The filtrate is concentrated, poured into water and extracted with ether. The ether solution is washed with dilute hydrochloric acid (1N), with dilute bicarbonate solution and finally with saturated potassium chloride solution. After evaporation in vacuo, 8.4 g of oil (IV) (with R denoting ethyl) is obtained.
Infrared: NH 3345; C=O 1735, 1635.
NMR: aromatic proton r 2.5 3.0(4), tertiary proton 4.0( 1) COCH- -CO 5.42(2) O-CH- -CH 643(4);
mass spectroscopy 372.2.
1 g of potassium t-butylate is dissolved in 24 ccm of t-butanol and at room temperature a solution of 3.1 g of (IV) in 24 ccm of t-butanol is slowly added. After an hour at room temperature the solution is poured into water and acidified with 2N hydrochloric acid, extracted with ether, washed with saturated potassium chloride solution and evaporated to dryness. The residue is recrystallized from methanol and 2.1 g (81%) of (la) (with R denoting ethyl) is obtained which has a melting point of 201C with decomposition.
IR: NH 3450, OH 3260, CO 1610.
NMR: aromatic protons 2.5 3.1 (4) O-CH -CH 576(2) O-CH -CH 8.75(3) mass spectroscopy 326 calculated: C 66.21 H 5.56 N 8.59. found: C 66.32 H 5.68 N 8.65.
Production of (lb):
2 g of the enol (la) is dissolved in 200 ccm of methylene chloride and an ethereal solution of diazomethane is slowly added at room temperature until a Fe(lll) reaction can no longer be observed. After allowing to stand for 10 minutes at room temperature, the organic phase is shaken first with dilute acetic acid, then with saturated bicarbonate solution and finally with saturated sodium chloride solution. The whole is then evaporated and the residue is taken up in ether. After standing in a refrigerator 350 mg of the isomeric crystalline enol ether is deposited. The mother liquor which is homogeneous according to thinlayer chromatography after evaporation contains about 1.5 g of crude (V) (71%). For characterization some of the mother liquor is chromatographed on silica gel and a crystalline produce (V) (with R denoting ethyl) is obtained in this way which has a melting point of l 18C.
NMR: NH 1' 0.55 (1) s, aromatic protons 2.45 3.05 m,
O-CH -CH 5.8(2) a,
OCH -CH 8.76 (3) tr.,
OCH 6.17 (3) s.
C M- N 0 340 mass spectroscopy 340.
500 mg of the enol ether (V) is dissolved in ccm of absolute dioxane and united under nitrogen with a solution of 300 mg of t-butyl malonate and 80 mg of sodium hydride in ccm of absolute dioxane. After 1 hour under reflux, decompositon is effected with dilute acetic acid and extraction with methylene chloride. The organic phase is shaken with saturated bicarbonate solution and then with saturated sodium chloride solution and dried over sodium sulfate. The solvent is then evaporated off in vacuo. The residue which remains is chromatographed on silica gel and from the fraction there is obtained with ether/petroleum ether (1:1) 230 mg of the triester (lb) (with R denoting ethyl and R denoting T-butyl). It has a melting point of 182C.
NMR: NH 1.9 (1), aromatic protons 2.43.0 (4),
OCH- -CH 5.5(2) q,
OCH --CH 8.6 (3) tr., O-C(CH;,)
CZZHHZWNZOT 524-6 mass spectroscopy 524.6.
calculated: C 66.39 H 6.92 N 5.34. found: C 66.32 H 7.16 N 5.43.
Production of chlorine derivatives (Vla) and (Vlb):
200 mg of the quinoline (11a) is dissolved in 5 ccm of dimethylformamide (absolute) and while cooling with ice 1 ccm of thionyl chloride is slowly added. After thirty minutes at room temperature, the whole is slowly poured into ice-cold saturated bicarbonate solution and extracted with methylene chloride. The methylene chloride phase is washed with saturated sodium chloride solution and evaporated in vacuo. The residue is recrystallized from methylene chloride/acetone and 190 mg (85%) of the chlorine derivative (Vla) (with R The following Examples illustrate the invention:
EXAMPLE 1 Production of compound (11a):
300 mg of the compound (Ia) with R denoting ethyl is dissolved in 25 ccm of dimethylformamide and 400 mg of potassium t-butylate is added to the solution. After aeration with oxygen, the whole is allowed to stand for 10 hours at room temperature, then poured onto'30 ccm of ice-water and clearly acidified with concentrated hydrochloric acid. The precipitate which forms slowly is suction filtered after some time, washed with acetone and finally with ether and in this way an amorphous product is obtained which is allowed to stand overnight in a methanol solution of hydrochlorid acid. The solvent is then evaporated and the product (Ila) with R denoting methyl is recrystallized from methanol. the yield is 50%. Melting point 230C with decomposition.
UV: 325,314 (qualitative) IR: C=O 1620, aromatic 1580 NMR: aromatic protons 1.9
(2) OCH 627(3),
calculated: C 62.57 H 4.33 N. 8.58. found: C 62.14 H 4.54 N 8.68
EXAMPLE 2 Production of compound (llb):
EXAMPLE 3 r temperature r 15 h Proton acqeptor 5 dissolved in 100 ccm dimethylformamide is heated for dficoinposed g f l l li l acld :l' F pyndone 12 hours at 50C in the presence of 500 mg LEWATIT envanve extracte met y l C Onde MP 5080 (a strongly basicion exchanger)'while pass sf gf dgonde phiise ls g h ing oxygen through. The ion exchanger is filtered off rate so mm ar.onate so t en y l0 and the filtrate evaporated to dryness under reduced rated. Recrystallization from an ether/acetone mixture Th t d f in I gives 380 mg (72%) of the quinolone of formula B. pressure" e resl ue 1S rec.ryS a lze mm me ano and 240 mg (46%) of the quinolone of formula H is ob- 4 tainecL By oxidizing the indole of formula C in the manner What is Claimed is! I described in Example 3 the quinolone of formula D is 15 1. A process for the production of a 5,6-benzo-yobtained in a 76% yield. pyridone having the formula:
id N v CO CH v l N o H f\ v Q I (10 C ri n CH 0 H cG 3 500 mg of the indolederivative of formula E above is dissolved in 100 ccm dimethylformamide, 200 mg so- N O damide is added, and the solution is allowed to stand at f room temperature under oxygen for hours. Dilute l acetic acid is carefully added to decompose the proton H CO2 acceptor and the product is extracted with methylene 3 3 chloride. Evaporation gives 280 mg (53%) quinolone of formula Fabove 1n Wl'llCl'l R denotes alkyl of from 1 to 3 carbons, and
R" denotes t-butyl Wl'llCll comprises subjecting an in- EXAMPLE 6 5O dole of the formula:
500 mg of the indole compound of formula C is dissolved in 100 ccm dioxane and then a Griguard compound of 200 mg o,o-dimethylbromobenzeneand 30 mg magnesium in 20 ccm dioxane is added. The mixture is allowed to stand at room temperature under oxygen for 15 hours. Dilute acetic acid is added to effect decomposition and methylene chloride is used as extractant. By evaporation of the solvent 320 mg I I] I A Y N V g H CO C H 2 2 3 of the quinolone derivative of formula D is obtained.
EXAMPLE 7 t i 500 mg of the indole derivativeof formula G above,
10 of lithium. sodium potassium, magnesium, or calcium in a liquid medium at a temperature of from 0 to 50C to form said compound II.

Claims (2)

1. THE METHOD FOR PRODUCING (-) VINCAMINE) WHICH COMHAVING THE FORMULA:
1. A PROCESS FOR THE PRODUCTION OF A 5,6-BENZO-Y-PYRIDONE
US206922A 1970-12-12 1971-12-10 5,6-Benzo-{65 -pyridone derivatives Expired - Lifetime US3892754A (en)

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DE19702061359 DE2061359A1 (en) 1970-12-12 1970-12-12 5,6-Benzo-gamma-pyridone derivatives and processes for their preparation
DE2156501A DE2156501A1 (en) 1970-05-14 1971-11-13 5,6-benzo-gamma-pyridone derivs - inters for anticarcinogenic cpds

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DE2534601C2 (en) * 1975-08-02 1987-01-22 Basf Ag, 6700 Ludwigshafen Process for the preparation of camptothecin and camptothecin derivatives
JPS635798U (en) * 1986-06-28 1988-01-14

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3234142A (en) * 1962-05-25 1966-02-08 Bayer Ag Optical brightening agents
US3634346A (en) * 1969-08-15 1972-01-11 Union Carbide Corp Oxidation of cyclic amines to lactams

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3234142A (en) * 1962-05-25 1966-02-08 Bayer Ag Optical brightening agents
US3634346A (en) * 1969-08-15 1972-01-11 Union Carbide Corp Oxidation of cyclic amines to lactams

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